Myelotoxicity is a prevailing, severe, complication of chemotherapy and is one of the factors that limit the administrable dose of the chemotherapeutic drug. It causes more life threatening patient morbidity and actual mortality than any other chemotherapeutic side effect and may result in an increased number of hospital stay days. In addition, drug induced myelosuppression limits the administration of larger, potentially more effective doses of chemotherapy to patients with malignancies. Several approaches to resolve this adverse event have included the use of lithium, prostaglandin E, interferon, lactoferrin and the growth factors granulocyte-macrophage colony stimulating factor (GM-CSF) and granulocyte-colony stimulating factor (G-CSF). To date, use of growth factors such as G-CSF is a standard therapy for cancer patients with neutropenia. It stimulates the proliferation and differentiation of hematopoietic progenitors and also controls the functional activities of neutrophils and macrophages. However, the G-CSF treatment is costly and as it is a recombinant protein, it has accompanying side effects.
Adenosine, an endogenous purine nucleoside, is ubiquitous in mammalian cell types. Adenosine present in the plasma and other extracellular fluids mediates many of its physiological effects via cell surface receptors and is an important regulatory protein. It is released into the extracellular environment from metabolically active or stressed cells. It is known to act through its binding to specific G-protein associated A1, A2 and A3 membranal receptors(1-2). The interaction of adenosine with its receptors initiates signal transduction pathways, mainly the adenylate cyclase effector system, which utilizes cAMP as a second messenger. While A1 and A3 receptors, which are coupled with Gi proteins, inhibit adenylate cyclase and lead to a decrease in the level of intracellular cAMP, the A2 receptor, which is coupled to Gs proteins, activates adenylate cyclase, thereby increasing cAMP levels(3).
Since specific surface receptors for adenosine are found in nearly all cells, almost all organ systems of the body are regulated to some extent by its local release. This includes regulation of the electrophysiological properties of the heart, sedation and suppression of neurotransmitter's release and regulation of rennin release and vascular tone in the kidney(4-7). Adenosine exerts various effects on the immune system including anti-inflammatory activity through the inhibition of cytokine release, inhibition of platelet aggregation, induction of erythropoietin production and modulation of the lymphocyte function(8-10). Further, adenosine was found to play a role in the modulation of some central nervous system (CNS) functions, in wound healing, in diuresis and in controlling pain. It was also demonstrated that adenosine is capable of inducing proliferation in a wide range of normal cell types(11-14). This modulation of cell growth is likely mediated through the adenylate cyclase effector system described above.
In a recent study it was found that adenosine acts as a chemoprotective agent, which activity is likely related to its capability to stimulate bone marrow cell proliferation. Further, it was found that adenosine exerted an inhibitory effect on the proliferation of tumor cells, apparently through G0/G1 cell cycle arrest and reduction of the telomeric signal(17-18). The dual effect has turned adenosine into an attractive concept for cancer treatment.